Ciliary neurotrophic factor and its receptors are differentially expressed in the optic nerve transected adult rat retina

Sarup, Vimal; Patil, Kiran; Sharma, S. C.

doi:10.1016/j.brainres.2004.03.030

Cited by 53 publications

(30 citation statements)

References 30 publications

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“…3A) in agreement with previous immunocytochemical observations (Sarup et al, 2004). Basal expression of LIF was unaltered in the absence of CNTF, but following injury, regulation of LIF expression was strikingly different in CNTF -/-as compared to wildtype animals (Fig.…”

Section: Lif Expression Is Upregulated Specifically In Cntf -/-Mice Fsupporting

confidence: 92%

Involvement of gp130‐associated cytokine signaling in Müller cell activation following optic nerve lesion

Kirsch

Trautmann

Ernst

et al. 2010

Glia

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Ciliary neurotrophic factor (CNTF) and the related cytokine leukemia inhibitory factor (LIF) have been implicated in regulating astrogliosis following CNS lesions. Application of the factors activates astrocytes in vivo and in vitro, and their expression as well as their receptors is upregulated after brain injury. Here, we investigated their function by studying Müller cell activation induced by optic nerve crush in CNTF- and LIF-deficient mice, and in animals with deficiencies in cytokine signaling pathways. In the retina of CNTF(-/-) mice, basal GFAP expression was reduced, but unexpectedly, injury-induced upregulation in activated Müller cells was increased during the first 3 days after lesion as compared to wild-type animals and this corresponded with higher phosphorylation level of STAT3, an indicator of cytokine signaling. The observation that LIF expression was strongly upregulated in CNTF(-/-) mice but not in wild-type animals following optic nerve lesion provided a possible explanation. In fact, additional ablation of the LIF gene in CNTF/LIF double knockout mice almost completely abolished early lesion-induced GFAP upregulation in Müller cells and STAT3 phosphorylation. Early Müller cell activation was also eliminated in LIF(-/-) mice, despite normal CNTF levels, as well as in mutants deficient in gp130/JAK/STAT signaling and in conditional STAT3 knockout mice. Our results demonstrate that LIF signaling via the gp130/JAK/STAT3 pathway is required for the initiation of the astrogliosis-like reaction of retinal Müller cells after optic nerve injury. A potential role of CNTF was possibly masked by a compensatory increase in LIF signaling in the absence of CNTF.

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Section: Lif Expression Is Upregulated Specifically In Cntf -/-Mice Fsupporting

confidence: 92%

Involvement of gp130‐associated cytokine signaling in Müller cell activation following optic nerve lesion

Kirsch

Trautmann

Ernst

et al. 2010

Glia

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“…LIF possesses a signal sequence and is released by cells (Knight, 2001). Since all components of a fully functional LIF receptor are expressed in RGCs (Sarup et al, 2004) and since LIF, like CNTF, strongly stimulates neurite outgrowth of RGCs in culture as shown in the current study, it is conceivable that glial-derived LIF contributes to the LI-induced stimulation of axon regeneration in the optic nerve. This hypothesis is supported by our observation that ONC in CNTF-deficient mice induced a stronger LIF expression compared with wild-type animals which was paralleled by increased neurite outgrowth in vitro and axon regeneration after ONC in vivo.…”

Section: Discussionsupporting

confidence: 57%

“…However, glial-derived factors other than CNTF may be additional contributors. In this context leukemia inhibitory factor (LIF) is of particular interest, since the LIF receptor components (gp130 and LIFR␤) are also part of the ternary CNTF receptor complex (Taupin et al, 1998;Heinrich et al, 2003;Sarup et al, 2004;Holtmann et al, 2005) and therefore LIF may be sufficient to stimulate axon growth of mature RGCs.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective and Axon Growth-Promoting Effects following Inflammatory Stimulation on Mature Retinal Ganglion Cells in Mice Depend on Ciliary Neurotrophic Factor and Leukemia Inhibitory Factor

Leibinger¹,

Müller²,

Andreadaki³

et al. 2009

J. Neurosci.

223

218

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After optic nerve injury retinal ganglion cells (RGCs) normally fail to regenerate axons in the optic nerve and undergo apoptosis. However, lens injury (LI) or intravitreal application of zymosan switch RGCs into an active regenerative state, enabling these neurons to survive axotomy and to regenerate axons into the injured optic nerve. Several factors have been proposed to mediate the beneficial effects of LI. Here, we investigated the contribution of glial-derived ciliary neurotrophic factor (CNTF) to LI-mediated regeneration and neuroprotection using wild-type and CNTF-deficient mice. In wild-type mice, CNTF expression was strongly upregulated in retinal astrocytes, the JAK/STAT3 pathway was activated in RGCs, and RGCs were transformed into an active regenerative state after LI. Interestingly, retinal LIF expression was correlated with CNTF expression after LI. In CNTF-deficient mice, the neuroprotective and axon growth-promoting effects of LI were significantly reduced compared with wild-type animals, despite an observed compensatory upregulation of LIF expression in CNTF-deficient mice. The positive effects of LI and also zymosan were completely abolished in CNTF/LIF double knock-out mice, whereas LI-induced glial and macrophage activation was not compromised. In culture CNTF and LIF markedly stimulated neurite outgrowth of mature RGCs. These data confirm a key role for CNTF in directly mediating the neuroprotective and axon regenerative effects of inflammatory stimulation in the eye and identify LIF as an additional contributing factor.

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“…Comparably, IL-6 binds to the IL-6 receptor to form a complex with two gp130 receptors. 27,32 Although all these receptor components are expressed by mature RGCs 16,26 and cytokines directly interact with RGCs in cell cultures, 16,27,31,34 expression of the α-receptors (LIFR, CNTFR, IL6R) is seemingly limited in RGCs. In fact, CNTFRα is reportedly downregulated in RGCs upon axotomy, potentially even decreasing their responsiveness towards this respective cytokine.…”

Section: Introductionmentioning

confidence: 99%

Hyper-IL-6: a potent and efficacious stimulator of RGC regeneration

Fischer

2016

Eye

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Mature retinal ganglion cells (RGCs) normally fail to regenerate injured axons and die soon after optic nerve injury. Research over the last two decades has demonstrated that application of IL-6-like cytokines or activation of respective downstream signaling pathways promote neuroprotection and optic nerve regeneration. However, the overall beneficial effects of natural cytokines remain usually rather moderate, possibly due to intrinsic signaling pathway inhibitors, such as PTEN or SOCS3, or a limited expression of specific cytokine receptors in RGCs. It was recently demonstrated that directly targeting the gp130 receptor, a common signalling receptor of all IL-6-like cytokines, induces stronger RGC axon regeneration in vitro and in vivo than other known growth-promoting treatments such as inflammatory stimulation or PTEN knockout. Remarkably, continuous expression of hyper-IL-6 (hIL-6) upon intravitreal AAV injection after nerve injury enables long-distance axon regeneration, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Thus, AAV-mediated hIL-6 delivery is so far one of the strongest single, post-injury treatments for the promotion of optic nerve regeneration and may be suitable for the development of novel, clinically applicable therapeutic treatments for human patients.

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Ciliary neurotrophic factor and its receptors are differentially expressed in the optic nerve transected adult rat retina

Cited by 53 publications

References 30 publications

Involvement of gp130‐associated cytokine signaling in Müller cell activation following optic nerve lesion

Involvement of gp130‐associated cytokine signaling in Müller cell activation following optic nerve lesion

Neuroprotective and Axon Growth-Promoting Effects following Inflammatory Stimulation on Mature Retinal Ganglion Cells in Mice Depend on Ciliary Neurotrophic Factor and Leukemia Inhibitory Factor

Hyper-IL-6: a potent and efficacious stimulator of RGC regeneration

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